Bladder cancer is the fifth most common cancer worldwide, with an estimated 70,980 new cases and 14,330 deaths occurring in the United States in 2009 (34). The prevalence of FGFR3 activating mutations and/or overexpression in bladder cancer and the large body of preclinical loss-of-function studies have implicated FGFR3 as an important oncogenic driver and a potential therapeutic target in this disease setting (12, 21-25). Despite of recent progresses toward clinical development of therapeutic agents targeting FGFR3, critical insights into how FGFR3 signaling contributes to bladder cancer development and progression remain to be elucidated.
FGFR3 belongs to a family of four structurally and functionally related receptor tyrosine kinases, which transduce signals from many of the 22 identified FGF polypeptides in human (1-3). Upon ligand binding, FGFR3 dimerizes and becomes autophosphorylated at specific tyrosine residues. This triggers the recruitment of adaptor proteins, such as FGFR substrate 2α (FRS2α), to the receptor, resulting in the activation of multiple downstream signaling cascades, including the canonical Ras-Raf-MAPK and PI3K-Akt-mTOR pathways (1-3). FGFR3 signaling plays critical roles during embryonic development and in the maintenance of tissue homeostasis, and regulates cell proliferation, differentiation, migration and survival in a context-dependent manner (3-4).
Aberrant activation of FGFR3 has been implicated in diverse physiological and pathological conditions. Gain-of-function mutation in FGFR3 is one of the most common genetic alterations in a spectrum of human congenital skeletal and cranial disorders (5-6). Dysregulation of FGFR3 via mutations or overexpression has also been linked with a variety of human cancers, including multiple myeloma positive for t(4; 14) (p16.3; q32) chromosomal translocation (7-10), bladder cancer (11-14), breast cancer (15), cervical carcinoma (11, 16), hepatocellular carcinoma (17), squamous non-small cell lung cancer (18, 19), and testicular tumors (20). In particular, somatic activating mutations in FGFR3 have been identified in 60-70% of papillary and 16-20% of muscle-invasive bladder tumors (13-14). Moreover, FGFR3 overexpression has been documented in a significant fraction of superficial as well as advanced bladder cancers (12-13, 21). Importantly, a plethora of loss-of-function studies demonstrate that pharmacological and genetic intervention of FGFR3 function blocks bladder cancer cell proliferation in culture and inhibits tumor growth in animal models (12, 22-25). Collectively, these data indicate that a subset of bladder cancer is addictive to FGFR3 activity, underscoring the importance of this receptor as a therapeutic target in bladder cancer. Indeed, both monoclonal antibodies and small molecule inhibitors against FGFR3 have recently been developed as a potential targeted therapy in this disease setting (26-28). Despite these recent advancements toward clinical development of anti-FGFR3 agents and the characterization of canonical signaling pathways emanating from cell surface FGFR3, at present there is very little information on how FGFR3 signaling contributes to bladder carcinogenesis. The precise molecular and cellular consequences downstream of FGFR3 activation remain to be elucidated.